The targeted repair or inactivation of damaged proto-oncogenes (oncogenes) may be a specific and effective treatment for neoplasia. My long-term goal is to understand bow oncogenes induce and maintain tumorigenesis. My strategy has been to generate a conditional transgenic model system using the tetracycline regulatory system to investigate how oncogene activation causes tumorigenesis and when continued activation is required to maintain a tumorigenic phenotype. I have focused on investigating how over-expression of the MYC proto-oncogene causes tumorigenesis. My hypothesis is that the mechanism by which MYC induces tumorigenesis will define when its continued expression is required to maintain a tumorigenic phenotype, and thus, when its inactivation will induce tumor regression. Recently I have shown that MYC-induced tumors regressed upon MYC inactivation (see Appendix, Feisher and Bishop, Molecular Cell, 1999). From these results, I conclude that there are circumstances when the inactivation of MYC can cause tumor regression. Now, I propose experiments to address the following three specific aims:(1) 1 will determine how MYC activation induces tumorigenesis in hematopoietic cells by influencing the cell cycle, genomic stability and apoptosis and how other oncogenes (p53-I-, p]9ARF-/-, ROAS, BCL2) cooperate with MYC to influence these same parameters. (2) I will determine how MYC inactivation causes tumor regression, if MYC re-activation permits tumor relapse, and if cooperating oncogenic events (p53-I-, p19ARF-/-, RAS, BCL2 ) prevent regression or promote relapse. (3) I will determine how MYC maintains a tumorigenic phenotype by examining if (MYC family members (N-, L-MYC), S-MYC or MYC mutants defective for specific functional domains or MYC 's transcriptional targets (ODC, eIF-4E, TERT) can functionally replace MYC. I will attempt to identify novel genes that can functionally replace MYC to maintain in part or whole its neoplastic phenotype. The results obtained from these studies will be useful in determining how MYC causes tumorigenesis and defining when the inactivation of MYC is likely to be effective in the treatment of human neoplasia.